Effect of azidocillin, erythromycin, clindamycin and doxycycline on postoperative complications after surgical removal of impacted mandibular third molars

Int. J. Oral Surg. 1980: 9: 157-165 (Key words: aZidaci//in; erythromycin; clindamycin; doxycyciine; antibiotics; surgery. oral)

Effect of azidocillin, erythromycin, clindamycin and doxycycline on postoperative complications after surgical removal of impacted mandibular third molars HANS BYSTEDT, CARL ERIK NORD AND AKE NORDENRAM Departments of Oral Surgery and Oral Microbiology, Karolillska Illstitute, alld Department of Bacteriology, National Bacteriological Laboratory, Stockholm, Swedell

Treatment of osteitis after surgical removal of the third molar of the mandible is still a clinical problem. A total of 140 patients undergoing operations for removal of an impacted third molar of the mandible, were included in a double-blind study. Placebo or antibiotics - azidocillin, erythromycin, clindamycin and doxycycline were given to the patients preoperatively and for the following 7 days. The concentrations in serum, alveolar serum and mandibular bone were measured and the postoperative courses - pain, trismus, swelling and wound-healing - were recorded. No correlation was obtained between the antibio·tic concentration and the postoperative complaints, except in the azidocillin group on day 2, in which fewer complaints were noticed in patients with high concentrations of the drug at the time of operations. The 80 patients in the antibiotic groups responded significantly better with respect to wound-healing than the 60 patients in the placebo groups. Only 15 operations lasted more than 15 min and the three of them which subsequently resulted in alveolitis were in the placebo groups. Antibiotics significantly reduced pain on day 7 postoperatively. In general, no statistically significant differences in trismus and swelling could be demonstrated between the patient groups. Ho,wever, there was a significant difference between the placebo and doxycycline groups with respect to swelling (day 2 postoperative, P < 0.01; day 5 postoperative, P < 0.05). Thus systemically administered antibiotics offered only slight advantages in routine operations of impacted third mandibular molars, but could decrease the rate of infections after traumatic operations. ABSTRACT -

(Received for publicatioll 5 June, accepted 7 September 1979)

Infections of the jaws are mostly of muItimicrobial origin, and the normal flora of the oral cavity is the major etiological cause 8. It is reasonable that any bacteria in the 0300-9785/80/030157-09$02.50/0

oral cavity could contaminate an intraoral wound 22 and it has been foundS that patients who develop alveolitis have higher preoperative and postoperative microbial @

1980 Munksgaard, Copenhagen

158

BYSTEDT, NORD AND NORDENRAM

counts than clinically normal patients. Other investigations have shown a decrease of alveolitis, when oral lavage is used1o ,31. Pain, trismus and swelling are common postoperative complaints connected with surgical removal of mandibular third molars. These symptoms can be aggravated by supervening infections, i.e. alveolitis which is still a clinical problem. The incidence of alveolitis associated with mandibular third molar extractions has ranged in various reports from 0.5 to 25 %1,3",10,21,24,20,31,32, and in women receiving oral contraceptives up to 45 %29. In order to prevent postoperative infection and reduce morbidity following removal of impacted mandibular third molars, different antibiotics, both local and systemic, have been used. Although the general opinion is that local chemotherapy may involve a risk of making the patients allergic and of selecting resistant bacteria, there are reports in which the use of local chemotherapy effectively eliminated the postoperative discomfort10 , 12, 13, 2S, 27, 28. The use of systemic prophylactic antibiotics in oral and maxillofacial surgery has been reported by many authors with various results 6,13,14,20, 3', but no study has attempted to evaluate the antibiotic concentration in the operated area with the incidence and nature of postoperative complications. The purpose of this investigation was to assess whether use of azidociIlin, erythromycin, clindamycin or doxycycline could reduce postoperative infection after surgical removal of impacted mandibular third molars.

Material and methods The experimental design was a double-blind clinical study and included both objective and subjective assessments.

79 males and 61 females (mean age 29· years, range 17-79) attending the Department of Oral Surgery, Huddinge University Hospital, Karolinska Institute, Stockholm, Sweden, for surgical removal of an impacted third molar of the mandible. The distribution between males and females was almost equal in the placebo and antibiotic groups. None of the subjects had any history of significant gastrointestinal or hepatic or renal disease. NQ other medication except analgesics was allowed during the investigation period. All patients had consented to the investigation.

DRUG ADMINISTRATION The operations were performed under lidocaine-adrenaline conduction anesthesia (Xylocaine-Adrenaline® 2 %, Astra, Sodertiilje, Sweden). The patients were given the antibiotic or placebo 60, 90 or 180 min before the operation and then daily for 7 days. The patients were divided into three groups, depending on the time difference of drug administration. The first group contained 40 patients assigned at random to azidocillin (Globacillin®, Astra, SOdertlilje, Sweden) and placebo groups. The patients received placebo or 750 mg azidocillin 60 min before the operation and then 750 mg every morning (9 a.m.) and night (9 p.m.) for 7 days. The second group contained 60 patients assigned at random to erythromycin stearate (Reciomycin®, Kabi, Stockholm, Sweden), cHndamycin (Dalacina®, Upjohn, Kalamazoo, Michigan, USA) and placebo groups. The patients received 500 mg erythtomycin or 300 mg clindamycin or placebo 90 min before the operation and then 250 mg erythromycin or 150 mg clindamycin or placebo four times per day, the first at 9 a.m. and the last at 9 p.m. for 7 days. The third group contained 40 patients assigned at random to doxycycline (Vibramycin®, Pfizer, New York, USA) and placebo groups. The patients received 200 mg doxycycline or placebo 180 min before the operation and then 100 mg doxycycline 0:1' placebo once a day at 9 a.m. for 7 days. The analgesic used in all cases was acetylsalicylic acid (Albyl® Selters, Leo, Helsingborg, Sweden) and the dosage was 0.5-1.0 g when it was needed.

PATIENTS

SAMPLING PROCEDURE FOR ASSAY OF ANTIBIOTICS

The study comprised 140 healthy outpatients,

Blood samples were obtained by filling hepa-

ANTIBIOTICS IN REMOVAL OF THIRD MOLARS rinized capillary tubes with capillary blood drawn from the finger tip. Samples were taken prior to administration of antibiotic or placebo and 30, 60, 120, 180, 240 min during the first day and then 2, 5 and 7 days thereafter at 8 a.m. Dental alveolar blood samples from the operation site were taken by the same technique. The specimens were obtained simultaneously with surgery, Le. 60 min after the dose of azidocillin of placebo, 90 min after the dose of erythromycin and clindamycin or placebo and 180 min after dose of doxycycline or placebo. After centrifugation of the samples, the serum was sucked off for measurement of the drug either on the same day or later after storage at -20°C. Bone specimens were taken at the same times as the dental alveolar blood samples from the operation site in the mandible by a trephining drill, dissected free of soft tissue and scraped free of marrow.

ANTIBACTERIAL DRUGS OF STANDARD SERIES Azidocillin (D-azidobenzylpenicillin, sodium salt batch 41, Astra, Sodertiilje, Sweden), erythromycin (erythromycin lactobionate, lot no. 22-120-DH, Kabi, Stockholm, Sweden), clindamycin (clindamycin hydrochloride, lot no. 8012, Upjohn, Kalamazoo, Michigan, USA), and doxycycline (doxycycline hydrochloride, lot no. 312-58710, Pfizer, Brussels, Belgium) were dissolved in 0.15 M phosphate buffer, pH 7.2, to give concentrations of 256.0 Ilg/ml of active drug. From these stock solutions, standard solutions were prepared in pooled human serum and human bone. The ranges of the standard series were 0.25-32.0 .ug/ml for azidocillin, 0.25-8.0 Ilg/ml for erythromycin, and 0.25-32.0 ,ug/ml for clindamycin and 0.5-16.0 .ug/ml for doxycycline.

ASSAY OF ANTIBIOTICS IN SERUM The serum concentrations were determined by an agar diffusion method using paper discs as diffusion centers15 • The test medium used was Bacto Penassay Seed Agar (DifCO') and indicator strains were Sarcina lutea ATCC 9341 for azidocillin, erythromycin and cIindamycin, and Bacillus cereus ATCC 11778 for doxycyline.

ASSAY OF ANTIBIOTICS IN BONE The piece of bone sample, obtained as a small standardized cylinder, was placed on agar sur-

159

faces inoculated with the respective indicator strain together with standard bone samples and incubated at 37°C for 18 h. The antibiotic concentrations were determined according to BySTEDT et al. 5

CLINICAL EXAMINATION Operations. All operations were carried out on Wednesday mornings by the same surgeon (H. B.) using local anesthesia, Xylocaine-Adrenaline 2 %, 3.6 ml, and a standardized operating technique. The duration of the operations was recorded. Pain. On the day of the operation and on days 2, 5 and 7 postoperatively, pain was recorded according to the following scale: I none or insignificant, II pain requiring no analgesics, III = severe pain requiring analgesics. . Trismus. Before the operation and on days 2, 5 and 7 postoperatively, the ability to open the mouth was determined. A vernier gauge was used to measure the distance between the right upper and lower central inciso'IS. The differences between pre- and postoperative measurements were used as measurements of trismus. Swelling. To oMain a reliable and accurate measurement of cheek swelling, a device constructed by LOKKEN et al. 20 was used. This device consists of a facial bow with bilateral vertical plates. The facial bow is locked to individual bite-blocks, which makes it possible to insert, remove and reinsert the device in exaci.Iy the same position at each measurement. The vertical plates are perforated by eight numbered adjustable plastic screw pins, which cover the areas where swelling normally occurs. The degree of facial swelling was obtained by subtraction of post- and preoperative measurements, representing the sum of the remaining lengths of the eight measuring pins outside the vertical plates. Wound-healing. Patients were examined on days 2, 5 and 7 for evidence of loose mucoperiosteal flap17 and alveolitis. Diagnosis of aIveolitis was made clinically on the basis of severe mandibular pain accompanied by necrotic debris or a denuded alveolus. Side effects. Patients were questioned at each examination regarding side effects such as fever, indisposition or diarrhea. Statistical analysis. All data have been handled by the Computer Department, Karolinska Institute, using Nord 10/Sintram III. Nonparametric methods, i.e. Mann-Whitney U-test, Spearman rank correlation coefficient and

=

=

BYSTEDT, NORD AND NORDENRAM

160

Kruskal-Wallis one-way analysis. Results were also analyzed according to the chi-square test.

Results CONCENTRATIONS OF ANTIBIOTICS IN CAPILLARY SERUM, ALVEOLAR SERUM AND MANDIBULAR BONE Azidocillin. The mean peak concentrations in capillary serum and alveolar serum of azidocillin at the time of the operation were 7.9 .ug/ml (range 2.7-14.0 pg/mt) and 7.9 ,ug/ml (range 2.5-13.4 ,ug/ml), respectively. The corresponding mean value for the mandibular bone concentrations was 0.2 Itg/g (range 0-0.5 Ilg/g). No azidocillin was detected in nine bone samples (Table 1). No antibiotic was detected in serum samples on days 2, 5 and 7 at 8 a.m. before the first dosage of the day. Erythromycin. The serum levels of erythromycin were found to vary within a wide range and three patients did not attain any measurable levels at the operation time. The maximum mean alveolar serum concentration of 0.7 ,ug/ml (range 0-3.3 Itg/ml) was recorded at the operation time. Mandibular bone concentrations were found in only six cases, with a maximum of 0.6 /-tg/ g (Table 1). The mean peak serum concentrations were on day 2, 0.2 Jig/ml (range 00.8 ,ug/ml), on day 5, 0.2 ,ltg/ml (range 0-

0.9 pg/ml) and on day 7, 0.1 /-tg/ml (range 0-0.7 ,ug/ml).

Clindamycin. The mean peak concentrations of clindamycin in capillary serum and alveolar serum at the time of operation were 2.4 Itg/ml (range 1.0-4.8 pg/ml) and 2.0 Itg/ml (range 1.0-4.0 ,ltg/ml), respectively. The corresponding mean values for the mandibular bone concentrations was 0.5 /-lg/ g (range 0-1.1 ,ltg/g). No antibiotic was detected in seven bone samples (Table 1). No serum concentrations were obtained on days 2, 5 and 7 at 8 a.m. before the first dosage on the day. Doxycycline. At the time of the operation, maximum mean levels in capillary serum and alveolar serum were 3.7 ,ltg/ml (range 1.1-8.0 ,ug/ml) and 3.2 p,g/ml (range 1.56.0 ,ltg/ml), respectively. The mean peak concentration in mandibular bone at the same time was 2.2 I[g/g (range 0-3.8 ltg/g). No doxycycline was found in four bone samples (Table 1). The mean peak serum concentrations on days 2 and 5 were 1.3 /-lg/ml and on day 7, 1.2 I-ig/ml with a range from 0 to 3.1 ,ltg/ml. ANTIBIOTIC CONCENTRATrONS AND POSTOPERATIVE COMPLAINTS No correlation was obtained between the antibiotic concentrations of alveolar serum and mandibular bone and the lack of post-

Table 1. Antibiotic concentrations in capillary serum, alveolar serum and mandibular bone at time of operation Antibiotic Azidocillin Erythromycin Clindamycin Doxycycline

Capillary serum ,ug/ml Range Mean 7.9 1.0 2.4 3.7

2.7-14.0 0* - 3.3 1.0- 4.8 1.1- 8.0

Alveolar serum ,ug/ml Range Mean 7.9 0.7 2.0 3.2

2.5-13.4 0 - 3.3 1.0- 4.0 1.5- 6.0

... In two patients, concentrations were obtained 30 min later.

Mandibular bone ,ugjg Range Mean 0.2 0.1 0.5 2.2

0-0.5 0'-0.6 0-1.1 0-3.8

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ANTIBIOTICS IN REMOVAL OF THIRD MOLARS

%

50 40 30

p

C p

P

A

D

E

D

A

20 10

DAY 2

DAY 5

7

Fig. 1. Distribution of patients experiencing pain (as percentage of whole group). Score II, pain requiring no analgesics, D. Score III, severe pain requiring analgesics, ~. P ;::: placebo, A :::: azidociIIin, E = erythromycin, C ;::: clindamycin and D == doxycycline.

operative complaints, trismus and swelling, except in the azidocillin group on day 2, in which fewer complaints were apparent in the case of patients with high concentration of the antibiotic at the time of operation. CLINICAL FINDINGS Operations. The time taken for operations did not differ significantly between the groups.

The average duration was 13 min in the placebo group, 12 min in the azidocillin group, 12 min in the erythromycin group, 10 min in the cIindamycin group and 12 min in the doxycycline group. Only 15 operations lasted more than 15 min, six in the antibiotic groups and nine in the placebo groups. Three of these 15 operations resulted in alveoIitis and were in the placebo groups.

mm 20

E pAC

D 10

p

A E

DAY 2 Fig. 2. Mean value and S.E.M. of trismus. P

clindamycin and D ;::: doxycycline.

p

C D

DAY 5

DAY 7

== placebo, A azidocillin, E

= erythromycin, C ==

162

BYSTEDT, NORD AND NORDENRAM

mm 30

p

20 p

D 10

DAY 2

A

E

c

D

DAY 5

P

DAY 7

Fig. 3. Mean value and S.E.M. of swelling. P := placebo, A = azidocillin, E:= erythromycin, C :=

c1indamycin, D := doxycycline.

Pain. On the day of surgery, when the effect of local anesthesia had worn off, all patients needed analgesics (acetylsalicylic acid 0.5-1.0 g). The number of patients who needed analgesics on the days 2 and 5 were equally distributed between the placebo groups and the antibiotic groups. The number of patients with pain were significantly fewer in the antibiotic groups than in the placebo groups on day 7 (P = 0.001) (Fig. 1); Trismus. Fig. 2 shows the mean value of the difference between the pre- and postoperative measurements of the mouth opening capacity. No significant differences of trismus were found between the patient groups. Swelling. There was a statistically significant difference on day 2 (P < 0.01) and on day 5 (P < 0.05) between the placebo group and doxycycline group. No other statistically significant differences could be seen between the groups (Fig. 3). Wound-healing. The distribution of alveolitis and loose mllcoperiosteal flap with necrotic margin in different patient groups

is shown in Table 2. Statistical analysis revealed significantly better results in the antibiotic groups (P < 0.01). Side effects. The side effects were mild, except in three cases where the patients go,t diarrhea, one in the azidocillin group and two in the clindarnycin group. The diarrhea, which started on day 5 or 6 after the operation, disappeared when the drug intake was stopped. One patient in the azidocillin group also got skin rashes. The tongues of three patients in the doxycycline group became brown-colored during antibiotic treatment, a side effect which disappeared a few days after the treatment was finished.

Discussion The present investigation was carried out in order to study the ability of antibiotics to modulate postoperative complaints, such as pain, swelling, trismus and impaired woundhealing. The four antibiotics, azidocillin, erythromycin, clindamycin and doxycycline, are all used in oral infections. Penicillin (azidocil·

163

ANTIBIOTICS IN REMOVAL OF THIRD MOLARS

Table 2. Distribution of alveolitis and loose mucoperiosteal flap in the different patient groups Placebo group No. % No complications Alveolitis Loose mucoperiosteal flap Total no. of patients

Antibiotic groups No. %

47

78

75

5 8

8

13

3

2

2

60

100

80

100

lin) which is a bactericidal antibiotic, is mostly used because of its good effect on bacteria isolated from oral infections 4 • Erythromycin is used in patients allergic to penicillin and its action is bacteriostatic. Clindamycin, which is bacteriostatic at low concentrations and bactericidal at lligher concentrations, can also be used in penicillin-allergic individuals and has an especially good effect in anaerobic infections3o ,33. A limitation to the use of clindamycin is the occurrence of pseudomembranous enterocolitis 1B • Doxycycline also represents an alternative to penicillins for treatment of oral infections. Doxycycline can penetrate even poorly vascularized tissues owing to its optimal lipid solubility, which facilitates transport across biological membranes. Doxycycline gives high concentrations in bone and in saliva5• The etiologic factors of postoperative complications after surgical removal of impacted mandibular third molars can be divided into two main groups - general factors and local factors 2• In this investigation the general factors could be excluded, since all patients were healthy. The local factors are trauma during the operation, infection at the operation or thereafter and increased fibrinolytic activity in the blood clot. Both trauma and infection can cause inflammation. If the inflammation is generated mainly by bacteria, antibiotics should be ideal, but if there is an aseptic traumatic inflammation, antibiotic treatment is of no value. Increased fibrinolytic activity is, according

94 4

to BIRN2, caused mostly by trauma. In this study, the trauma was almost equal in all patient groups, when the operating time was used as a measurement of trauma. The correlation between pain and bone infection is well known. On the seventh day postoperatively, significantly less pain was found in patients treated with antibiotics. This contrasts with CuRRAN et aL6, who found no difference between the antibiotic treated group and the control group at any time postoperatively. Acetylsalicylic acid, which was the analgesic used in all cases, has an effect both on pain and inflammation. Since all patients needed this analgesic on the day of operation and the numbers of patients who needed this analgesic on the days immediately following the operation were equal between the placebo groups and antibiotic groups, the effect of analgesics can be neglected in the present investigation. In this investigation, only doxycycline displayed a significant reduction in the degree of swelling on days 2 and 5 postoperatively. Azidocillin, erythromycin and clindamycin showed slight effects on swelling, though none was statistically significant. The effect of antibiotics on swelling is probably due to the reduction of postoperative infections. In only a few earlier investigations of antibiotic treatment of oral infections has swelling been recorded postoperatively. Thus, NORDENRAM et al. 25 , using neomycin-bacitracin cones in third molar sockets, found a significant reduction of swelling, while MACGRE-

164

BYSTEDT, NORD AND NORDENRAM

et a1. 23 using neomycin, found no difference between antibiotic group and placebo group. Systemic administration of benzylpenicillin and erythromycin produced no reduction in swelling6• No difference in trismus was noticed between the antibiotic groups and the placebo groups. Similar findings have been reported by CURRAN et al. 6 • Inability to open the jaws postoperatively is mainly a result of trauma more than infection. GREENFIELD et al. l1 showed that trismus reached its maximum about 16 h after the operation and then slowly decreased, while alveolitis normally will be diagnosed about 3 days after the operation. Alveolitis and loose mucoperiosteal flap are considered to be disturbances in the wound-healing process caused by surgical trauma, infection or increased fibrinolytic activity2. Many investigators have also described a correlation between traumatic operation and alveolitis14, 19, 21, 25, 32. In contrast to other investigators 6,26, significantly less postoperative infections in patients treated with systemic antibiotic were seen in the present investigation. Antibiotics given systemically are retained in the blood clots formed in tooth sockets and the antibiotic concentration will remain constant if the antibiotic treatment is continued16 • The antibiotic concentration in the operated region is important in inhibiting microorganisms which are capable of causing postoperative infections. The dental alveolar serum concentrations of the four antibiotics in the present investigation exceeded the minimum inhibitory concentrations of most microorganisms isolated from mandibular osteitis4 • The persistent serum concentrations of doxycycline on days 2, 5 and 7 depend on its longer half-life and the concentrations of erythromycin at the same times may depend on a delay in its resorption. This study shows that systemically admin-

GOR

istered antibiotics offer only slight advantages in routine operations of impacted third mandibular molars, but can decrease the rate of infections after traumatic operations. Acknowledgments - The authors are most indebted to Ulf Brodin, B.Sc., and Elisabet Berg, B.Sc., Computer Department, Karolinska Institute, for their help with the statistical analysis.

References 1.

2.

3. 4.

5.

6.

7.

8.

BELINFANIB, L. S., MARLOW, C. D., MYERS, W. & ROSENBERG, C.: Incidence of dry socket complication in third molar removal. J. Oral Surg. 1973: 31: 106-108. BIRN, H.: Etiology and pathogenesis of fibrinolytic alveolitis ("dry socket"). Int. J. Oral Surg. 1973: 2: 1(211)-57(267). BROWN, L. R., MER.1u:LL, S. S. & ALLiEN, R. E.: Microbiological study of intraoral wounds. J. Oral Surg. 1970: 28: 89-95. BYSTEDT, H., DAHLBACK, A. & NORD, C. E.: Concentrations of azidocillin, erythromycin, doxycycline and clindamycin in dental alveolar serum after single oral doses. Int. J. Oral Surg. 1977: 6: 65-74. BYSTEDT, H., DAHLBACK, A., DORNBUSCH, K. & NORD, C. E.: Concentrations of azidocillin, erythromycin, doxycycline and clindamycin in human mandibular bone. Int. J. Oral Surg. 1978: 7: 442-449. CuImAN, J. B., KE.NNiE'IT, S. & YOUNG, A. R.: An assessment of the use of prophylactic antibiotics in third molar surgery. Int. J. Oral Surg. 1974: 3: 1-6. FREITAG, V.: Komplikationshaufigkeit nach Weisheitszahnenentfernung. Dtsch. zahniirtztl. Z. 1967: 22: 1030-1035. FROSTELL, G. & No'RD, C. E.: Oral rnikrobiolagi. Almqvist & Wiksell, Stockholm

1975. 9. GARROD, L. P., LAMBERT, H. P. & O'GRADY, P.: Antibiotic and chemotherapy. 4th ed. Livingstone, Edinburgh 1973.

10.

D. R., KlLOORE, D. S., P,ANZiER, J. D. & ATKINSON, W. H.: Prevention of

GOLDMAN,

dry socket by local application of lincomycin in Gelfoam. Oral Surg. 1973: 35: 472-

474. 11. GREENFIELD, B. E. & MOORE, J. R.: Elec-

ANTIBIOTICS IN REMOVAL OF THIRD MOLARS tromyographic study of postoperative trismus. J. Oral Surg. 1969: 27: 92-98. 12. HALL, H. D., BILDMAN, B. S. & HAND, C. D.: Prevention of dry socket with local application of tetracycline. J. Oral Surg. 1971: 29: 35-37. 13. HANDTMANN, VON, S. & SCHULTE, W.: Die primare Heilung intraoraler Knochendefekte unter dem Einfluss lokaler und allgemeiner antibakteriellen Prophylaxe. Disch. zahniirztl. Z. 1976: 31: 566-570. 14. HELLEM, S. & NOROENRAM, A.: Prevention of postoperative symptoms by general antibiotic treatment and local bandage in removal of mandibular third molars. Int. J. Oral Surg. 1973: 2: 273-278. 15. JALLING, B., MALMBORG, A. S., LINDMAN, A. & Bomus, L. 0.: Evaluation of a micromethod for determination of antibiotic concentrations in plasma. Eur. J. CUn. Pharmacal. 1972: 4: 150-157. 16. JUNIPER, R. P.: Penicillin-the duration of its activity in blood clots. Br. J. Oral Surg. 1972: 9: 222-227. 17. KHOSLA, M. & GOUGH, J. E.: Evaluation of three techniques for the management of postextraction third molar sockets. Oral Surg. 1971: 31: 189-198. 18. I.E FROCK, 1. L., KLAINER, A. S., CmBN, S., GAINER, R. B., OMAR, M. & ANDERSSON, W.: The spectrum of colitis associated with lincomycin and clindamycin therapy. J. Inject. Dis. 1975: 131: 108-115. 19. LILLY, G. E., OSBON, D. B., RAEL, E. M., SAMUELS, H. S. & JoNiBS, J. C.: Alveolar osteitis associated with mandibular third molar extractions. J. Am. Dent. Assoc. 1974: 88: 802-806. 20. LoKKEN, P., OLSEN, 1., BRUAS,ET, I. & NORMAN-PEDERSEN, K: Bilateral surgical removal of impacted lower third molar teeth as a model for dmg evaluation: A test with Ibuprofen. Eur. J. CUn. Pharmacal. 1975: 8: 209-216. 21. MACGREGOR, A. J.: Aetiology of dry socket: A clinical investigation. Br. J. Oral Surg. 1968: 6: 49-58. 22. MACGREGOR, A. 1. & HART, P.: Effect of bacteria and other factors on pain and swelling after removal of ectopic mandibular. third molars. J. Oral Surg. 1969: 27: 174-179. 23. MACGREGOR, A. J. & HUTCHINSON, D.: The effect of nivemycin on pain and swelling following lower third molar removal. Br. J. Oral Surg. 1973: 10: 321-325.

165

24. MARTIS, C., KARABOUTA, 1. & LAZARIDIS, N.: Extraction of impacted mandibular wisdom teeth in the presence of acute infection. Int. J. Oral Surg. 1978: 7: 541-548. 25. NORDBNRAM, A., SYDNES, G. & ODEGAA:lID, J.: Neomycin-bacitracin cones in impacted third molar sockets. Int. J. Oral Surg. 1973: 2: 279-283. 26. PATERSON, J. A., CARDa, V. A. & ST.RAnGOS, G. T.: An examination of antibiotic prophylaxis in oral and maxillofacial surgery. J. Oral Surg. 1970: 28: 753-759. 27. QUINLEY, J. P., ROGER, R. Q. & GoRES, R. J.: "Dry socket" after mandibular odontectomy and use of soluble tetracycline hydrocloride. Oral Sllrg. Oral Med. Oral Pathal. 1960: 13: 38-42. 28. Run, J., BAGGESEN, H. & MOLLER, J. F.: Effect of the sulfa cones and suturing on the incidence of pain after removal of impacted lower third molars. J. Oral Surg. 1963: 21: 219-226. 29. SCHOW, S. R.: Evaluation of postoperative localized osteitis in mandibular third molar surgery. Oral Surg. 1974: 38: 352-358. 30. SCHUREN, N. J., PANZER, J. D. & ATKINSON, W. H.: A comparison of clindamycin and penicillin V in the treatment of oral infections. J. Oral Surg. 1974: 32: 503-505. 31. SWEET, J. B. & BU1"LER, D. P.: Predisposing and operative factors: Effect on the incidence of localized osteitis in mandibular third molar surgery. Oral Sllrg. 1978: 46: 206-215. 32. VAN GoaL, A. V., TEN BOSCH, J. J. & BOERING, G.: Clinical consequences of complaints and complications after removal of the mandibular third molar. Int. J. Oral Surg. 1977: 6: 29-37. 33. WHARTON, M. R. & BEDDOW, F. H.: Clindamycin for acute osteomyelitis in children. Pastgrad. Med. J. 1975: 51: 166-168. 34. ZALLEN, R. D. & STRADER, R. J.: The use of prophylactic antibiotics in extraoral procedures for mandible prognathism. J. Oral Surg. 1971: 29: 178-179.

Address:

Hans Bystedt KaroUnska lnstitutet Odontologiska Fakulteten Box 4964 S 14104 Huddinge Sweden